Macrophages induce AKT/β-catenin-dependent Lgr5+ stem cell activation and hair follicle regeneration through TNF

Nat Commun. 2017 Mar 27:8:14091. doi: 10.1038/ncomms14091.


Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen-anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+ HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5+ HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • CX3C Chemokine Receptor 1 / metabolism
  • Female
  • Hair Follicle / physiology*
  • Macrophages / physiology*
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Regeneration*
  • Stem Cells / physiology*
  • Tumor Necrosis Factor-alpha / physiology*
  • beta Catenin / metabolism


  • Antigens, Ly
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Lgr5 protein, mouse
  • Ly-6C antigen, mouse
  • Receptors, G-Protein-Coupled
  • Tumor Necrosis Factor-alpha
  • beta Catenin
  • Proto-Oncogene Proteins c-akt